Advisor

Date

Type

Department

Degree Level

Statistics

Abstract

The rapidly growing world population and high rate of unintended pregnancy worldwide (~50%) suggest that currently available contraceptive measures are insufficient to meet the needs of people at different stages of their reproductive lives, with different ethnic, cultural and religious backgrounds, as well as economic status. Safer, more effective, convenient, and affordable contraceptive methods are needed. Currently available contraceptive pills are hormone-based and designed specifically for women. Male contraceptive pills remain unavailable. Functional disruptions of late spermiogenesis lead to production of deformed and/or non-functional sperm and thus male infertility, but rarely cause testis shrinkage. Based on this finding, we first proposed in 2009 that late spermiogenesis-specific gene products are ideal targets for male non-hormonal contraceptive drugs. SPEM1 is a protein exclusively expressed in elongated spermatids, and inactivation of Spem1 gene leads to male infertility in mice due to deformed sperm characterized by bent-back heads wrapped by residual cytoplasm, and that Spem1-null sperm cannot develop vigorous and long-lasting progressive motility. To find a compound that can cause sperm deformation similar to that seen in Spem1-null sperm, we embarked on an extensive search for known drug candidates documented to cause sperm deformation as a side effect during preclinical testing or clinical trials. After testing numerous compounds, we found a natural compound purified from a Chinese herb that can cause sperm head-bent-back deformation almost identical to that seen in Spem1-null mice. We named the compound spermdeformin 1 (SD-1). Mice efficacy tests showed that oral administration of SD-1 at 0.8mg/kg of B.W. caused male infertility due to sperm deformation and a lack of motility in ~4 weeks. Continuous SD-1 treatment maintained male infertility and fertility could recover in ~4 weeks after treatment ended. During SD-1 treatment, no significant decrease in testis weight or sperm counts was observed although close to 100% of epididymal sperm became deformed and displayed minimal or no progressive motility. Moreover, no discernable side effects were observed, and pups fathered by males whose fertility recovered after SD-1treatment were normal and healthy. Our data suggest that SD-1 is a very promising oral male contraceptive agent.